Vitamin D and the Regulation of Iron Metabolism: Implications for Anemia of Inflammation Open Access
Smith, Ellen Margaret (2016)
Published
Abstract
Vitamin D deficiency and anemia are highly prevalent in the general population, and several chronic diseases including cardiovascular disease and chronic kidney disease carry increased risk for both conditions. Vitamin D deficiency has been identified as a risk factor for anemia in epidemiologic studies, and in vitro studies suggest that vitamin D may reduce cytokine release and hepcidin expression, markers involved in the etiology of anemia of inflammation. The purpose of this dissertation was to 1) examine the association between vitamin D status and anemia in generally healthy adults; 2) evaluate the effect of vitamin D supplementation on markers involved in the etiology of anemia; and 3) test the effect of vitamin D supplementation on hemoglobin concentrations in a population at risk for vitamin D deficiency and anemia. These aims were addressed via cross-sectional analyses exploring the association between 25-hydroxyvitamin D [25(OH)D] concentrations and anemia/hemoglobin, in a racially diverse cohort of employees of Emory University, and among Vietnamese women of reproductive age. We then used a double-blind placebo-controlled trial of healthy adults randomized to receive a one-time oral dose of 250,000 IU of vitamin D3 or placebo to test the effects of vitamin D supplementation on plasma pro-inflammatory cytokine, hepcidin, and ferritin concentrations measured at baseline and one week later. Finally, we tested the effect of vitamin D supplementation on hemoglobin and hepcidin concentrations using a double-blind, placebo-controlled trial of critically ill adults randomized to receive 500,000 IU D3, 250,000 IU D3, or placebo. In generally healthy adults, serum 25(OH)D concentrations <20 ng/mL were associated with lower hemoglobin concentrations and increased odds of anemia, particularly anemia of inflammation. High-dose vitamin D3 supplementation reduced circulating hepcidin concentrations after one week among healthy adults; there were no changes in cytokine or ferritin concentrations. In critically ill adults, treatment with high-dose vitamin D3 resulted in increased hemoglobin concentrations over time; hepcidin concentrations did not change over time. These results provide preliminary evidence of a role for vitamin D in the regulation of iron metabolism. Larger clinical trials are warranted to fully evaluate the therapeutic efficacy of vitamin D in improving anemia.
Table of Contents
CHAPTER 1: Introduction 1
Vitamin D 1
Sources and metabolism of vitamin D 1
Functions of vitamin D 4
Vitamin D requirements 6
Vitamin D deficiency and toxicity 7
Iron and Anemia 9
Sources and metabolism of iron 10
Functions of iron 13
Iron requirements 14
Iron deficiency and toxicity 14
Anemia 17
Purpose of Research 20
CHAPTER 2: Vitamin D and anemia: insights into an emerging association 24
Abstract 25
Introduction 26
Mechanism of action in the vitamin D - anemia association 26
Inflammation and hepcidin 27
Erythropoiesis 29
Other calciotropic hormones and anemia 30
Fibroblast Growth Factor-23 (FGF-23) 30
Parathyroid Hormone (PTH) 31
Epidemiology of the vitamin D deficiency and anemia association 31
Association of vitamin D with subtypes of anemia and racial differences in the association 32
Clinical trials 33
Implications for clinical practice 34
Conclusions 35
Key points 36
CHAPTER 3: Vitamin D deficiency is associated with anaemia among African Americans in a U.S. cohort 42
Abstract 44
Introduction 45
Materials and Methods 46
Study population 46
Data collection 47
Definitions 48
Statistical analysis 49
Results 51
Participant characteristics 51
Associations of vitamin D status with markers of iron status 53
Association of vitamin D status with anaemia 53
Association of vitamin D status with subtypes of anaemia 54
Discussion 55
CHAPTER 4: Dietary vitamin D intake, vitamin D status, and associations with anemia in women of reproductive age in rural northern Vietnam 73
Abstract 75
Introduction 76
Methods and materials 78
Study population 78
Data collection and processing 79
Dietary intake 79
Biochemical and anthropometric measurements 79
Demographic data 80
Definitions 81
Statistical analyses 82
Results 83
Participant characteristics 83
Distribution and determinants of dietary vitamin D intake 83
Associations of vitamin D intake with hemoglobin and anemia 84
Association of dietary vitamin D intake with 25(OH)D status 85
Determinants of 25(OH)D concentration and association of 25(OH)D with hemoglobin and anemia 86
Discussion 87
CHAPTER 5: High-dose vitamin D3 reduces circulating hepcidin concentrations: a pilot, randomized, double-blind, placebo-controlled trial in healthy adults 99
Abstract 101
Introduction 103
Materials and Methods 104
Subjects and protocol 104
Analytic procedures 105
Statistical analysis 106
Results 107
Participant characteristics 107
Effect of high-dose vitamin D on pro-inflammatory cytokine concentrations 108
Effect of high-dose vitamin D on plasma hepcidin concentrations 108
Effect of high-dose vitamin D on plasma ferritin concentrations 109
Discussion 109
CHAPTER 6: High-dose vitamin D3 administration is associated with increases in hemoglobin concentrations in mechanically ventilated critically ill adults: a pilot, double-blind, randomized placebo-controlled trial 122
Abstract 123
Introduction 125
Methods 126
Study design and participants 126
Data collection 128
Statistical analysis 129
Results 130
Sensitivity analyses 132
Discussion 132
CHAPTER 7: Discussion and conclusion 141
Key points 141
Strengths and limitations 145
Implications of this research 147
Future directions 151
Populations to study 152
Form and dose of vitamin D, duration of study 154
Iron and vitamin D biomarkers 156
Other mechanisms of action of vitamin D 156
Interplay of vitamin D with other regulators of iron metabolism 159
Lifestyle factors and functional outcomes 160
Conclusion 161
REFERENCES 163
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